X-linked hypophosphatemia (vitamin d-resistant rickets) is a human disease caused by a mutant dominant gene on the X-chromosome. One principal defect is impaired renal tubular reabsorption of phosphate which leads to increased urinary phosphate and reduced plasma phosphate. There are reports of intestinal malabsorption of calcium and phosphate in children but not adults with this disease. A mutant gene (Hyp) in mice has many features of the human disease. The Hyp gene is also X-linked and dominant. The afflicted mice are dwarfed and hae impaired renal tubular reabsorption of phosphate, hypophosphatemia and osteomalacic bone disease. We are excited about our recent finding of low intestinal vitamin D-dependent calcium binding protein in the Hyp mice. This occurs during their rapid growth phase and normalizes when the animals gain adult size and sexual maturity. In other systems this protein correlates with the plasma 1,25-(OH)2-vitamin D levels and the rate of calcium absorption. In the Hyp mice, this period of rapid growth is when the skeletal mineralization rate lags behind that of normal mice. We propose that there is impaired intestinal absorption of calcium and phosphate in juvenile but not adult Hyp mice. We propose further that this impaired absorption leads to undermineralization of the skeleton in the critical period of rapid growth. We feel the bone disease results from at least 2 mechanisms: the low renal tubular reabsorption of phosphate and the low intestinal absorption. This will be tested by balance studies and intestinal transport studies in juvenile mice. Stimuli for intestinal transport such as 1,25-(OH)2-vitamin D and parathyroid hormone will be measured. The responsiveness of the intestine to 1,25-(OH)2-vitamin D will be evaluated. Whether sexual maturity is connected with normalization of the intestinal problem will be tested by gonadectomy and sex hormone administration. Proof of this concept in Hyp mice may lead to new treatments for children with this disease aimed more at improving the intestinal status than in normalizing their plasma phosphate.